Anti-viral aromatic O-alkylated oximes, ethers and thioethers

ABSTRACT

Compounds of the formula ##STR1## These compounds are useful for inhibiting the growth or replication of retroviruses such as HIV.

This is a continuation-in-part of U.S. application Ser. No. 08/346,819,filed on Nov. 30, 1994, U.S. Pat. No. 5,663,199.

FIELD OF THE INVENTION

This invention relates to novel aromatic O-alkylated oximes, ethers andthioethers. In particular, this invention relates to novel aromaticO-alkylated oximes, ethers and thioethers useful as anti-viral agents.More particularly, this invention relates to novel aromatic O-alkylatedoximes, ethers and thioethers useful as agents against certainretroviruses such as the members of the group of Human ImmunodeficiencyViruses (HIV).

BACKGROUND OF THE INVENTION

Retroviruses are viruses whose replication requires the transcription ofviral RNA into DNA using the viral reverse transcriptase moleculesattached to the viral RNA. This reverse transcription is the opposite ofnormal transcription which makes RNA from DNA.

Known retroviruses include HIV-1, HIV-2, the herpes family of viruses,HTLV-1 and cytomegalovirus (CMV). HIV, the virus which is presentlybelieved to cause acquired immunodefiency syndrome (AIDS), is consideredone of the principle threats to human life and health worldwide.

Various anti-HIV compounds have been proposed as useful in the treatmentand prevention of AIDS, e.g., zidovudine (AZT), didanosine (ddI),zalcitabine (ddc), nevirapine, and dextran sulfate. However, none of theproposed compounds have been proven to be totally effective in thetreatment or prevention of AIDS. For example, the three currently FDAapproved compounds for the treatment of AIDS, i.e., AZT, ddI and ddC,can all cause undesirable side effects in a patient, such as inhibitionof bone marrow cell growth, and their effectiveness is limited by virusmutation.

U.S. Pat. No. 5,268,389 describes certain thiocarboxylate estercompounds useful for inhibiting the growth or replication of HIV.

It is the purpose of this invention to provide novel aromaticO-alkylated oximes, ethers and thioethers, useful as anti-viral agents.

It is also the purpose of this invention to provide a method forinhibiting or preventing the growth or replication of humanimmunodeficiency viruses using the novel aromatic O-alkylated oximes,ethers and thioethers.

Finally, it is also the purpose of this invention to providecompositions useful for inhibiting or preventing the growth orreplication of human immunodeficiency viruses, comprising the novelaromatic O-alkylated oximes, ethers and thioethers.

DESCRIPTION OF THE INVENTION

This invention relates to a compound of the formula ##STR2## wherein Qis ##STR3## or --XR';

X is oxygen or sulphur;

R¹ is hydrogen, halogen, C₁ -C₄ alkyl or C₁ -C₄ alkoxy;

R² is hydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, C₃ -C₄ alkenyloxy,C₃ -C₄ alkynyloxy, mono-, di- or tri- halomethyl, trifuluoromethoxy, C₁-C₄ alkylthio, C₃ -C₄ branched alkylthio, nitro, or cyano;

R³ is hydrogen or C₁ -C₄ alkyl;

R⁴ is C₃ -C₆ alkenyl, C₃ -C₆ alkynyl, C₁ -C₈ haloalkyl, C₁ -C₈alkoxyalkyl, C₁ -C₈ alkylthioalkyl, C₁ -C₈ hydroxyalkyl, C₁ -C₈acyloxyalkyl, C₁ -C₈ aroyloxyalkyl, C₁ -C₈ carboxyalkyl, C₁ -C₈alkylcarboxyalkyl, C₆ -C₁₂ arylcarboxyalkyl, C₁ -C₈ aminoalkyl, C₁ -C₈alkylaminoalkyl, C₁ -C₈ dialkylaminoalkyl, C₁ -C₈ trialkylsilylalkyl,wherein each of the aforementioned alkyl moieties may be straight-chainor branched; C₃ -C₈ cycloalkyl, C₁ -C₆ alkylphenyl, C₇ -C₁₂ arylalkyl,C₇ -C₁₂ alkarylalkyl, or heterocyclylalkyl, wherein the heterocyclicmoiety is morpholinyl, piperidinyl, pyrrolidinyl, piperazinyl, oxiranyl,oxetanyl, furanyl, tetrahydropyranyl or tetrahydrofuranyl;

R' is C₁ -C₈ haloalkyl, C₁ -C₈ haloalkenyl, C₁ -C₈ alkoxyalkyl, C₁ -C₈alkylthioalkyl, C₁ -C₈ hydroxyalkyl, C₁ -C₈ acyloxyalkyl, C₁ -C₈aroyloxyalkyl, C₁ -C₈ aminoalkyl, C₁ -C₈ alkylaminoalkyl, C₁ -C₈dialkylaminoalkyl, C₁ -C₈ trialkylsilylalkyl, wherein each of theaforementioned alkyl moieties may be straight-chain or branched; C₁ -C₆alkylphenyl, C₇ -C₁₂ arylalkyl, C₇ -C₁₂ alkarylalkyl, orheterocyclylalkyl, wherein the heterocyclic moiety is morpholinyl,piperidinyl, pyrrolidinyl, piperazinyl, oxiranyl, oxetanyl, furanyl,tetrahydropyranyl or tetrahydrofuranyl;

R⁵ is hydrogen, halo, methyl, mono-, di- or tri-halomethyl;

R⁶ is

1) R^(Z) --NH--, wherein R^(Z) is ##STR4## wherein R^(a) and R^(b) areindependently hydrogen or C₁ -C₆ alkyl; and Z¹ is O or S; or ##STR5##wherein Z² is O or S; and R^(A) is:

a) fully unsaturated, partially or fully reduced or substitutedoxathiinyl, furanyl, dithiinyl, dioxinyl, thienyl, thiazolyl, oxazolyl,isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl, pyrrolyl, imidazolyl,pyranyl, oxathiazinyl, oxadiazolyl, or indolyl;

b) substituted or unsubstituted, linear or branched C₁ -C₈ alkyl, C₂ -C₈alkenyl, C₂ -C₈ alkynyl, C₁ -C₈ alkoxy, C₂ -C₈ alkenyloxy, C₂ -C₈alkynloxy, or C₁ -C₈ mono- or di-alkylamino; C₃ -C₇ cycloalkyl, C₃ -C₇cycloalkyl C₁ -C₆ alkyl, C₃ -C₇ cycloalkenyl, unsubstituted orsubstituted by C₁ -C₆ alkyl or C₇ -C₈ phenylalkyl; or

c) aryl, aralkyl, aryloxyalkyl, or cycloalkylaryloxy wherein each alkylmoiety contains from 1 to 10 carbon atoms and each aryl moiety isnaphthyl, phenyl or phenyl substituted by one or more halo, C₁ -C₈alkyl, carboxyl, C₁ -C₈ haloalkyl, C₁ -C₈ alkylthio, phenyl, nitro,amino, C₁ -C₈ alkoxycarbonylamino, hydroxyl, acetyl, acetyloxy, phenoxy,C₁ -C₈ alkoxycarbonyl or C₁ -C₈ alkylcarbonyl;

(d) R⁷ --W--, wherein

W is O, NH or NR^(f) wherein R^(f) is C₁ -C₄ alkyl; and R⁷ is linear orbranched, unsubstituted or halo-substituted C₁ -C₈ alkyl, C₂ -C₈alkenyl, C₂ -C₈ alknyl, C₃ -C₇ cycloalkyl C₁ -C₆ alkyl, C₃ -C₇cycloalkenyl unsubstituted or substituted by C₁ -C₆ alkyl, unsubstitutedphenyl or phenyl substituted by halo, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,carboxyl, C₁ -C₈ alkythio, phenyl, nitro, amino, hydroxyl, acetyl,acetyloxy, phenoxy, C₁ -C₈ alkoxycarbonyl, or C₁ -C₈ alkylcarbonyl;furanylalkyl, tetrahydrofuranylalkyl, oxetanylalkyl, or oxiranylalkyl;

e) R⁸ --W¹ --R^(e), wherein

R^(e) is a linear or a branched C₁ -C₆ alkylidene;

W¹ is O or S; and

R⁸ is linear or branched C₁ -C₄ alkyl;

f) R⁹ R¹⁰ --N--R^(e), wherein

R^(e) is as defined above; and R⁹ and R¹⁰ are independently linear orbranched C₁ -C₄ alkyl; ##STR6## wherein

R^(e) is as defined above;

W² is O, S, NH, NR¹¹ or CR¹² R¹³ ; wherein R¹¹ is linear or branched C₁-₄ alkyl; R¹² and R¹³ are independently hydrogen or linear or branchedC₁ -C₄ alkyl; and

n' and m are independently 1, 2 or 3;

h) R¹⁴ --O₂ --C--R^(e), wherein

R^(e) is as defined above; and R¹⁴ is linear or branched C₁ -C₆ alkyl,C₃ -C₆ alkenyl, or C₃ -C₆ alkynyl; or C₃ -C₇ cycloalkyl, C₃ -C₇cycloalkyl C₁ -C₆ alkyl, or C₃ -C₇ cycloalkenyl, unsubstituted orsubstituted by C₁ -C₆ alkyl;

i) U--R^(e) --, wherein

R^(e) is as defined above; U is hydroxyl, acyloxy, aryloxy,arylsulphonyloxy, nitro, cyano or trimethylsilyl;

j) 1-adamantyl, 2-adamantyl or bornyl;

k) Ar¹ --R^(e) --, wherein

R^(e) is as defined above; and

Ar¹ is phenyl or phenyl substituted independently with one to threehalogen, mono-, di- or tri- halomethyl, nitro, C₁ -C₄ alkyl, C₃ -C₄alkenyl, C₁ -C₄ alkyloxy, C₃ -C₄ alkenyloxy, or C₃ -C₄ alkynyloxy.

Preferred compounds are those compounds wherein R⁶ is ##STR7## Z² is Oor S; and

R^(A) is

a) fully unsaturated, partially or fully reduced or substitutedoxathiinyl, furanyl, dithiinyl, dioxinyl, thienyl, thiazoyl, oxazoyl,isoxazoyl, isothiazoyl, thiadiazolyl, pyrazolyl, pyrrolyl, pyranyl,oxathiazinyl, or oxadiazolyl;

b) linear or branched C₁ -C₈ alkyl, C₃ -C₈ alkenyl, C₃ -C₈ alkynyl, C₁-C₈ alkoxy, C₃ -C₈ alkenyloxy, C₃ -C₈ alkynloxy, or C₁ -C₈ mono- or di-alkylamino; C₃ -C₆ cycloalkyl or C₃ -C₆ cycloalkenyl;

c) phenyl or phenyl substituted by one or more halo, C₁ -C₈ alkyl, C₁-C₈ haloalkyl, C₁ -C₈ alkylthio, phenyl, amino, hydroxyl, carboxyl,acetyl, acetyloxy, C₁ -C₈ alkoxycarbonyl, C₁ -C₈ alkylcarbonyl orphenoxy; C₇ -C₈ phenylalkyl or C₇ -C₈ phenoxyalkyl.

More preferred are those compounds wherein R^(A) is

a) dihydro-3-oxathiinyl, furanyl, dihydrofuranyl, thienyl, pyrrolyl,dihydro-2-dithiinyl, or dihydro-2-dioxinyl, which can be substituted byone to three C₁ -C₄ alkyl or C₁ -C₄ alkoxyalkyl groups;

b) linear or branched C₁ -C₈ alkyl, C₂ -C₈ alkenyl, C₃ -C₈ alkynyl, C₁-C₈ alkoxy, C₃ -C₈ alkenyloxy, C₃ -C₈ alkynyloxy or C₁ -C₈ mono- ordi-alkylamino; C₃ -C₆ cycloalkyloxy or C₃ -C₆ cycloalkenyloxy; or

c) phenyl or phenyl substituted by one or more halo, C₁ -C₈ alkyl, C₁-C₈ haloalkyl, C₁ -C₈ alkylthio, carboxyl, amino, C₁ -C₈ alkoxycarbonyl,hydroxyl, C₁ -C₈ alkylcarbonyl, phenyl or phenoxy.

Particularly preferred are those compounds wherein R⁶ ##STR8##

Z² is O or S;

R¹ is hydrogen; fluoro; or methyl;

R² is hydrogen, chloro, fluoro, or methyl;

R³ is hydrogen or methyl;

R⁴ is cyclopentyl or cyclohexyl;

R⁵ is hydrogen; and

R¹⁵ is methyl, ethyl or propyl.

Additionally preferred compounds are the furan, thiophene and pyrrolederivatives of the compound of formula I wherein R⁶ is: ##STR9##

Z² is O or S;

X¹ is O, S, NH or N-methyl,

R¹⁶ is hydrogen, methyl, ethyl, 1,1-dimethylethyl, fluoro, chloro,carboxyl, acetamido, cyano, C₁ -C₆ alkylthio, C₁ -C₆ haloalkoxy, C₁ -C₆acyloxy, (C₁ -C₆ alkoxy)carbonyl, or (C₁ -C₆ alkyl)carbonyl; and

R¹⁷ and R¹⁸ are independently hydrogen or methyl.

More preferred furan, thiophene and pyrrole derivatives are thosewherein R¹, R³ and R⁵ are hydrogen, R² is halogen, R⁴ is C₃ -C₆ alkenylor C₃ -C₆ alkynyl, which can be linear, branched or cyclic, and Z² is S.

Also preferred are the compounds of formula I wherein R⁶ is: ##STR10##

Z² is O or S;

R¹⁹, R²⁰, R²¹, and R²² are independently hydrogen or halogen, preferablyhydrogen; and

R²³ is hydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, mono, di- ortri-haloalkoxy, C₁ -C₄ haloalkyl, C₁ -C₄ alkylthio, amino, C₁ -C₈alkylcarbonylamino, hydroxyl, acetyl, acetyloxy, or acetylamino,preferably hydrogen, methyl, ethyl, chloro, iodo, amino, bromo, fluoro,methylthio, methoxy, difluoromethoxy, or hydroxy.

Also preferred as compounds of this invention are the derivatives ofacyclic carboxamides or carbamates of the compound of formula I whereinX, Z², R¹, R², R³, R⁴ and R⁵ are as recited above for formula I and R⁶is ##STR11## wherein R^(A) is a linear or branched C₃ -C₆ alkyl, C₃ -C₆alkenyl, C₁ -C₆ alkoxy, C₃ -C₆ alkenyloxy, C₃ -C₆ alkynyloxy, C₃ -C₆mono- or di-alkylamino, or C₃ -C₆ alkynyl; phenyl, C₇ -C₈ phenylalkyl,C₇ -C₈ phenoxyalkyl, C₃ -C₇ cycloalkyl, or C₃ -C₇ cycloalkenyl.

More preferred compounds are the compounds of formula I wherein R-- ishydrogen or fluoro; R⁴ is C₃ -C₆ alkenyl or C₃ -C₆ alkynyl, which may belinear, branched or cyclic; R⁶ is ##STR12## R^(A) is a linear orbranched C₃ -C₆ alkyl, C₃ -C₆ alkenyl, C₃ -C₆ alkynyl, C₃ -C₆ alkoxy, C₃-C₆ alkenyloxy or C₃ -C₆ alkynyloxy; C₇ -C₈ phenylalkyl, C₇ -C₈phenoxyalkyl, C₃ -C₆ cycloalkyl, or C₃ -C₇ cycloalkenyl.

Especially preferred compounds of this invention are the compounds offormula I wherein R¹ -R⁵ are hydrogen; R⁴ is C₃ -C₆ alkenyl or C₃ -C₆alkynyl, which may be linear, branched or cyclic; R⁶ is ##STR13## R^(A)is a linear or branched C₃ -C₆ alkyl, C₃ -C₆ alkoxy, C₃ -C₆ alkenyloxy,C₃ -C₆ alkynyloxy, C₃ -C₆ cycloalkyl, or C₃ -C₆ cycloalkenyl.

Further preferred compounds of this invention are the compounds offormula I wherein R¹ and R⁵ are hydrogen; R² is chloro or C₁ -C₄ alkoxy;R⁶ is ##STR14## R^(A) is dihydro-3-oxathiinyl, furanyl, thienyl,substituted by one to three C₁ -C₄ alkyl groups; Q is XR' wherein R' isC₁ -C₄ mono-haloalkyl, C₁ -C₄ di-haloalkyl, C₁ -C₄ mono-haloalkenyl, orC₁ -C₄ di-haloalkenyl.

The compounds of this invention are useful for the inhibition of thegrowth or replication of retroviruses, particularly humanimmunodeficiency viruses such HIV-1, in vitro and in vivo. The compoundsare useful in the therapeutic or prophylactic treatment of diseasescaused by retroviruses, such as acquired immune deficiency syndrome oran HIV infection in a human or other mammal.

It is intended that the scope of this invention encompass all isomers,including positional or stereoisomers, of any compound of formula Iexhibiting isomerism. It is also intended that any novel processes orintermediates for synthesizing said compounds be included within thescope of this invention.

GENERAL SYNTHETIC METHODS

Compounds of formula ##STR15## wherein Z² is O and R^(A) is oxathiinyl,furanyl, thienyl, pyrrolyl, other heterocyclyl, or substituted phenyl,can be prepared from the appropriate carboxylic acid, R^(A) --COOH, andan aniline derivative, i.e; ##STR16## by employing one of the methodsknown in the art of amide bond formation. For example, the carboxylicacid can be converted to an acid halide, such as the acid chloride,R^(A) COCl, which can then be reacted with the aniline derivative toform the amide. The amide forming reaction is carried out in anappropriate solvent, such as methylene chloride, toluene, methyl ethylketone, tetrahydrofuran, dimethylformamide or acetonitrile, at atemperature of about 0° C. to about 100° C.

It is usually preferable to carry out the reaction in the presence of abase, such as triethylamine or pyridine. Other reactive derivatives ofthe carboxylic acid can be employed: for example the anhydride of thecarboxylic acid or a mixed anhydride, such as alkoxycarbonyloxyderivative, can be reacted with the aniline derivative. Alternatively,the carboxylic acid and aniline derivative can be reacted directly inthe presence of a condensing agent such as dicyclohexylcarbodiimide toform the amide.

The aniline derivatives can be prepared by reduction of thecorresponding nitro compounds by well-known methods, for example withhydrogen and a catalyst, such as Raney nickel or platinum, or with ametal-acid combination, such as iron or tin and hydrochloric or aceticacid. Oxime ethers are made from the corresponding aldehyde byconventional methods. An exception is in the preparation of tertiaryo-alkyl oximes which are made by the action of an unsubstituted oximeand a tertiary alcoholic ester under acid catalysis in a suitablesolvent such as THF, dioxane or DME. A suitable acid catalyst would behydrochloric, sulphuric or perchloric acid.

Other compounds of this invention in which R^(A) is an alkoxy can beprepared by reacting the appropriate aniline derivative with analkoxycarbonyl chloride, under conditions essentially similar to thoseused for reaction of an acid chloride with the aniline derivative. Theycan also be prepared by reacting the appropriate isocyanate derivativewith an alcohol. The isocyanate can be prepared by reacting the anilinederivative or a suitable salt thereof, such as the hydrochloride, withphosgene or a phosgene substitute, such as trichloromethylchloroformate.

Compounds of this invention wherein R^(A) is alkoxy and Z² is sulphurcan be similarly prepared using alkoxy thiocarbonyl chloride underconditions described above or from the appropriate isothiocyanatederivative and an alcohol.

Thiocarboxaniliides of this invention wherein Z² is S and R^(A) isfuranyl, thienyl, pyrrolyl, other heterocyclyl or substituted phenyl,can be prepared starting from the corresponding amide and reacting itwith a sulfurating agent such as Lawesson's reagent or phosphoruspentasulphide in a suitable solvent such as toluene, xylene, DME,pyridine, or the like.

The following examples are provided to illustrate the synthesis of thecompounds of the present invention.

EXAMPLE I

The following Tables 1a and 1b list representative compounds that wereprepared using the methods described above.

                  TABLE 1a                                                        ______________________________________                                         ##STR17##                                                                    No.  R.sup.A     Z.sup.2                                                                              R.sup.3                                                                            R.sup.4    mp °C.                         ______________________________________                                        1    2-CH.sub.3 -3-Furanyl                                                                     O      H    CH.sub.2 CCH                                                                             135-136                               2    "           S      H    CH.sub.2 CHCH.sub.2                                                                      88-89                                 3    "           S      H    CH.sub.2 CCH                                                                             79-80                                 4    "           S      H    CH.sub.2 C.sub.6 H.sub.5                                                                 131-133                               5    "           S      H    CH.sub.2 CO.sub.2 C(CH.sub.3).sub.3                                                      130-131                               6    "           S      R    C.sub.5 H.sub.9 (cyclo)                                                                  73-75                                 ______________________________________                                    

                  TABLE 1b                                                        ______________________________________                                         ##STR18##                                                                    No.  R.sup.A   Z.sup.2                                                                              X   R.sup.2                                                                            R.sup.4    mp °C.                       ______________________________________                                        7    (CH.sub.3).sub.2 CHO                                                                    S      O   Cl   CHF.sub.2  110-115                             8    "         S      O   Cl   COCH(CH.sub.3).sub.2                                                                     89-91                               9    "         S      O   Cl   CH.sub.2 COCH.sub.3                                                                      104-108                             10   "         S      O   Cl   CH.sub.2 C(NOH)CH.sub.3                                                                  101-105                             ______________________________________                                    

IN VITRO SCREENING RESULTS

Representative compounds of this invention were tested for anti-viralactivity by subjecting them to standard National Cancer Institute("NCI") in vitro screening procedures. Two blanks were run with eachtest. The NCI test for agents active against HIV is designed to detectagents acting at any stage of the virus reproduction cycle.

In the test assay, small amounts of HIV are added to T4 lymphocytecells. The assay measures the amount of T4 lymphocytes "killed" by HIVcytolysis. Since a complete cycle of viral reproduction is necessary to"kill" the T4 lymphocyte cells, agents that interfere with viralreproduction will protect the cells from cytolysis.

The NCI system is automated in several features to accomodate largenumbers of candidate agents and is generally designed to detect anti-HIVactivity. Compounds that degenerate or are rapidly metabolized in theculture conditions do not show activity in this screen. All tests arecompared with at least one positive (AZT-treated) control done at thesame time under identical conditions.

The Test Procedure

1) The test compound was dissolved in dimethyl sulfoxide and diluted1:100 in cell culture medium before serial half-log₁₀ dilutions wereprepared. T4 lymphocytes (CEM cell line) were then added to the cellculture medium, and, finally, after a brief interval, HIV-1 was added,resulting in a 1:200 final dilution of the test compound. Uninfectedcells in the cell culture medium containing the test compound (i.e.,minus HIV-1) were used as a toxicity control, and infected cells in thecell culture medium without the test compound and uninfected cells inthe cell culture medium without the test compound, were used as basiccontrols.

2) The cultures were incubated at 37° C. in a 5% carbon dioxideatmosphere for 6 days.

3) The tetrazolium salt, XTT, was added to all wells, and the cultureswere then incubated to allow formazan color development by viable cells.

4) Individual wells were analyzed spectrophotometrically to quantitateformazan production, and were also viewed microscopically for detectionof viable cells and confirmation of protective activity.

5) Virus-infected cells exposed to the test compound were compared withnoninfected cells exposed to the test compound, and with otherappropriate controls (infected cells not exposed to the test compoundand noninfected cells not exposed to the test compound, wells containingonly the test compound in the cell culture medium, and so on) on thesame plate. These are the first and second blanks described below.

6) Data were reviewed in comparison with other tests done at the sametime and a determination concerning activity was made. In the firstblank, HIV and T4 lymphocytes in cell culture medium, were incubatedtogether to measure the infectivity of the virus. The viability of thecells was measured after holding for six or seven days. In an"effective" test, most cells were infected before the holding period wascomplete.

In the second blank, the T4 lymphocytes in cell culture medium and thetest compound (with no HIV-1) were incubated together to measure thetoxicity of the drug to the cellline. The viability of the cells wasmeasured as a function of concentration of the compound, afterincubation for seven days. The concentration of the test compound thatresults in 50% inhibition of cell growth is defined as its IC₅₀.

Finally, the protective effects of the test compounds were measured.Each cell culture and test compound were incubated with the virus andthe viability of the cells was measured as a function of compoundconcentration after incubation for six or seven days. The concentrationof the test compound that results in 50% "control," i.e., a 50%reduction of the viral cytopathic effect, is defined as its EC₅₀. Thetherapeutic index TI₅₀ was calculated as IC₅₀ /EC₅₀.

Concentrations of test compounds required for between 20 and 50%reduction of the viral cytopathic effect can also be determined. Suchcompounds are classified as moderately active. Compounds with less than20% control are considered inactive.

The compounds were tested to determine their reduction of HIV cytopathiceffect on the human cell line CEM. Tests were done by innoculating thesecell lines in-well (IW), i.e., the test compound and CEM cells weremixed on a test plate and the virus was added a short time later.

Screening Data for Test Compound Exhibiting Inhibition of HIV

The preceding protocol was carried out with all of the compoundsdescribed above in the Examples, all of which showed some significantactivity in at least one of the tests. The test results (molar) for allthe tested compounds are shown in Table 2 as IC₅₀, EC₅₀ and TI₅₀.

                  TABLE 2                                                         ______________________________________                                        Compound  IC.sub.50 (M)                                                                              EC.sub.50 (M)                                                                           TI.sub.50                                    ______________________________________                                        1         1.60 × 10.sup.-5                                                                     3.30 × 10.sup.-6                                                                  5                                                      1.80 × 10.sup.-5                                                                     3.50 × 10.sup.-6                                                                  5                                                      >2.30 × 10.sup.-5                                                                    3.90 × 10.sup.-6                                                                  >6                                                     >2.30 × 10.sup.-5                                                                    3.70 × 10.sup.-6                                                                  >6                                           2         >1.60 × 10.sup.-5                                                                    1.10 × 10.sup.-8                                                                  >1400                                                  >1.60 × 10.sup.-5                                                                    2.00 × 10.sup.-8                                                                  >770                                                   >1.60 × 10.sup.-5                                                                    4.50 × 10.sup.-8                                                                  >340                                                   >1.60 × 10.sup.-5                                                                    1.20 × 10.sup.-8                                                                  >1300                                        3         1.60 × 10.sup.-5                                                                     4.70 × 10.sup.-8                                                                  340                                                    1.60 × 10.sup.-5                                                                     3.80 × 10.sup.-8                                                                  440                                                    >2.20 × 10.sup.-5                                                                    1.30 × 10.sup.-7                                                                  >170                                                   2.10 × 10.sup.-5                                                                     1.10 × 10.sup.-7                                                                  190                                          4         >7.10 × 10.sup.-6                                                                    1.00 × 10.sup.-6                                                                  >7                                                     >7.10 × 10.sup.-6                                                                    1.60 × 10.sup.-6                                                                  >4                                                     >7.10 × 10.sup.-6                                                                    1.30 × 10.sup.-6                                                                  >5                                                     >7.10 × 10.sup.-6                                                                    1.10 × 10.sup.-6                                                                  >7                                           5         >2.40 × 10.sup.-5                                                                    2.00 × 10.sup.-5                                                                  >1                                                     >2.40 × 10.sup.-5                                                                    --        --                                                     1.90 × 10.sup.-5                                                                     4.40 × 10.sup.-6                                                                  4                                                      2.30 × 10.sup.-5                                                                     --        --                                           6         >1.40 × 10.sup.-5                                                                    2.50 × 10.sup.-7                                                                  >58                                                    >1.40 × 10.sup.-5                                                                    2.40 × 10.sup.-7                                                                  >59                                                    >1.40 × 10.sup.-5                                                                    1.80 × 10.sup.-7                                                                  >78                                                    >1.40 × 10.sup.-5                                                                    8.40 × 10.sup.-8                                                                  >170                                         7         3.47 × 10.sup.-5                                                                     2.62 × 10.sup.-6                                                                  13                                                     4.64 × 10.sup.-5                                                                     8.37 × 10.sup.-6                                                                  6                                                      3.22 × 10.sup.-5                                                                     --        --                                                     3.33 × 10.sup.-5                                                                     5.78 × 10.sup.-6                                                                  6                                            8         5.56 × 10.sup.-5                                                                     --        --                                                     5.13 × 10.sup.-5                                                                     2.80 × 10.sup.-5                                                                  2                                                      4.17 × 10.sup.-5                                                                     2.54 × 10.sup.-5                                                                  2                                                      4.75 × 10.sup.-5                                                                     1.81 × 10.sup.-5                                                                  3                                            9         7.70 × 10.sup.-5                                                                     2.70 × 10.sup.-6                                                                  28                                                     >1.20 × 10.sup.-4                                                                    2.00 × 10.sup.-6                                                                  >61                                                    >1.20 × 10.sup.-4                                                                    4.60 × 10.sup.-6                                                                  >26                                                    >1.20 × 10.sup.-4                                                                    1.10 × 10.sup.-6                                                                  >110                                                   1.20 × 10.sup.-4                                                                     3.30 × 10.sup.-6                                                                  36                                           10        --            9.7 × 10.sup.-8                                                                  --                                                     --            8.8 × 10.sup.-8                                                                  --                                                     --            2.0 × 10.sup.-7                                                                  --                                                     --            1.6 × 10.sup.-7                                                                  --                                           ______________________________________                                    

EXAMPLE II

The following Table 3 lists representative compounds 11-27 preparedaccording to the methods described above in Example I.

                  TABLE 3                                                         ______________________________________                                         ##STR19##                                                                    No.  R.sup.A      Z.sup.2                                                                             X   R.sup.2                                                                             R'                                          ______________________________________                                        11   2-methyl-3-thienyl                                                                         S     O   CN    2-chloro-2-propenyl                         12   2-methyl-3-furanyl                                                                         S     O   Cl    "                                           13   "            S     O   CH.sub.3                                                                            "                                           14   "            S     O   Cl    3,3-dichloro-2-propenyl                     15   5,6-dihydro-2-                                                                             O     O   Cl    "                                                methyl-1,4-                                                                   oxathiin-3-yl                                                            16   2-methyl-3-furanyl                                                                         S     S   Cl    "                                           17   "            O     S   Cl    "                                           18   "            O     O   Cl    3-chloro-2-butenyl                          19   "            O     O   OCH.sub.3                                                                           3,3-dichloro-2-propenyl                     20   2-methyl-3-thienyl                                                                         O     O   Cl    "                                           21   "            S     O   Cl    "                                           22   2-methyl-3-furanyl                                                                         S     O   Cl    3-chloro-2-butenyl                          23   5,6-dihydro-2-                                                                             S     O   OCH.sub.3                                                                           3,3-dichloro-2-propenyl                          methyl-1,4-                                                                   oxathiin-3-yl                                                            24   2-methyl-3-thienyl                                                                         S     O   OCH.sub.3                                                                           "                                           25   5,6-dihydro-2-                                                                             O     O   OCH.sub.3                                                                           "                                                methyl-1,4-                                                                   oxathiin-3-yl                                                            26   2-methyl-3-furanyl                                                                         S     O   OCH.sub.3                                                                           "                                           27   "            S     O   Cl    3-(trifluoro-methyl)-2-                                                       butenyl (E)                                 ______________________________________                                    

IN VITRO SCREENING

Cells and Viruses

Human lymphocyte CEM cells were obtained from the American Type CultureCollection and grown in RPMI 1640 medium supplemented with 10% (v/v)inactivated fetal calf serum (Gibco), 2 mM L-glutamine (FlowLaboratories), and 0.075% (v/v) NaHCO3 (Flow Laboratories). Cells weresubcultured every 3 to 4 days.

HIV-1(III_(B)) was kindly provided by R. C. Gallo and M. Popovic(National Cancer Institute, Bethesda, Md.). The selection andcharacterization of the HIV-1 RT mutant strains were done as follows:HIV-l/100-Ile ("100-Ile") was selected for resistance against TIBOR82150 as described in Balzarini et al, Virology 192: 246-253 (1993);HIV-1/103-Asn ("103-Asn") was selected for resistance against TIBOR82913 as described in Balzarini et al, Virology 192: 246-253 (1993);HIV-1/106-Ala ("106-Ala") was selected for resistance against nevirapineas described in Balzarini et al, J. Virol. 67: 5353-5359 (1993);HIV-1/Lys-138 ("Lys-138") was selected for resistance against TSAO-m³ Tas described in Balzarini et al, Virology 192: 246-253 (1993) andBalzarini et al, Proc. Nat. Acad. Sci. USA 90: 6952-6956 (1993);HIV-1/181-Cys ("181-Cys") was selected for resistance against pyridinoneL-697,661 as described in Balzarini et al, Virology 192: 246-253 (1993);and HIV-1/188-His ("188-His") was selected for resistance against HEPTas described in Balzarini et al, Mol. Pharmocol. 44: 694-701 (1993).188-His was then further converted to HIV-1/188-Leu("188-Leu") uponfurther passage in cell culture in the absence of the HEPT.

Antiviral activity of the test compounds in cell cultures

CEM cells were suspended at ≈300,000 cells per ml of culture medium andinfected with CEM cells were suspended at ≈300,000 cells per ml ofculture medium and infected with approximately 100 50% cell cultureinfective doses of HIV-III_(B) or one of the HIV-1 RT mutant strainsdescribed above. Then 100 μl of the infected cell suspensions was addedto 200 μl microtiter plate wells containing 100 μl of appropriate serial(5-fold) dilutions of the test compounds. The inhibitory effect of thetest compounds on HIV-1 induced syncytium formation in CEM cells wasexamined microscopically on day 4 post infection. The 50% effectiveconcentration (EC₅₀) was defined as the test compound concentration thatinhibits syncytium formation in the HIV-1-infected cell cultures by 50%.

                  TABLE 4                                                         ______________________________________                                        Antiviral Activity of Compounds 11-26                                         EC.sub.50 (μg/ml).sup.a                                                          HIV-1                              103-                                 Cmpd. (III.sub.B)                                                                           138-Lys 181-Cys                                                                             106-Ala                                                                             100-Ile                                                                              Asn 188-Leu                          ______________________________________                                        11    0.03    0.13    0.44  0.2   0.2   0.4  2.0                              12    0.047   0.26    1.07  0.51  0.7   0.65 2.0                              13    0.09    0.6     1.47  0.67  0.95  0.75 2.0                              14    0.0085  0.04    0.16  0.055 0.14  0.28 2.0                              15    1.2     2.0     2.0   2.0   2.0   2.0  2.0                              16    0.005   0.03    0.13  0.025 0.023 0.08 2.0                              17    0.093   0.68    2.0   0.8   0.93  2.0  2.0                              18    0.045   0.32    0.65  0.15  0.7   2.5  10.0                             19    0.25    10.0    8.0   2.0   5.0   10.0 10.0                             20    0.09    0.95    2.5   1.2   0.53  2.0  2.0                              21    0.007   0.075   0.23  0.065 0.065 0.4  2.0                              22    0.003   0.008   0.043 0.012 0.04  0.09 0.9                              23    0.27    3.5     2.0   2.0   1.8   2.5  2.0                              24    0.005   0.13    0.13  0.09  0.09  1.6  2.0                              25    4.0     10.0    10.0  10.0  10.0  10.0 10.0                             26    0.012   0.05    0.25  0.077 0.075 1.6  10.0                             ______________________________________                                         .sup.a 50% effective concentration (i.e., compound concentration required     to inhibit virusinduced cytopathicity by 50%)                            

What is claimed is:
 1. A compound of the formula ##STR20## wherein Q is##STR21## or --XR'; X is oxygen or sulphur;R¹ is hydrogen, halogen, C₁-C₄ alkyl or C₁ -C₄ alkoxy; R² is hydrogen, halogen, C₁ -C₄ alkyl, C₁-C₄ alkoxy, C₃ -C₄ alkenyloxy, C₃ -C₄ alkynyloxy, mono-, di- or tri-halomethyl, trifuluoromethoxy, C₁ -C₄ alkylthio, C₃ -C₄ branchedalkylthio, nitro, or cyano; R³ is hydrogen or C₁ -C₄ alkyl; R⁴ isheterocyclylalkyl, wherein the heterocyclic moiety is morpholinyl,piperidinyl, pyrrolidinyl, piperazinyl, oxiranyl, oxetanyl, furanyl,tetrahydropyranyl or tetrahydrofuranyl; R' is C₁ -C₈ haloalkyl, C₁ -C₈haloalkenyl, C₁ -C₈ alkoxyalkyl, C₁ -C₈ alkylthioalkyl, C₁ -C₈hydroxyalkyl, C₁ -C₈ acyloxyalkyl, C₁ -C₈ aroyloxyalkyl, C₁ -C₈aminoalkyl, C₁ -C₈ alkylaminoalkyl, C₁ -C₈ dialkylaminoalkyl, C₁ -C₈trialkylsilylalkyl, wherein each of the aforementioned alkyl moietiesmay be straight-chain or branched; C₁ -C₆ alkylphenyl, C₇ -C₁₂arylalkyl, C₇ -C₁₂ alkarylalkyl, or heterocyclylalkyl, wherein theheterocyclic moiety is morpholinyl, piperidinyl, pyrrolidinyl,piperazinyl, oxiranyl, oxetanyl, furanyl, tetrahydropyranyl ortetrahydrofuranyl; R⁵ is hydrogen, halo, methyl, mono-, di- ortri-halomethyl; and R⁶ is 1) R^(Z) --NH--, wherein R^(Z) is ##STR22##wherein R^(a) and R^(b) are independently hydrogen or C₁ -C₆ alkyl; andZ¹ is O or S; ##STR23## wherein Z² is O or S; and R^(A) is:a) fullyunsaturated, partially or fully reduced or substituted oxathiinyl,furanyl, dithiinyl, dioxinyl, thienyl, thiazolyl, oxazolyl, isoxazolyl,isothiazolyl, thiadiazolyl, pyrazolyl, pyrrolyl, imidazolyl, pyranyl,oxathiazinyl, oxadiazolyl, or indolyl; b) substituted or unsubstituted,linear or branched C₁ -C₈ alkyl, C₃ -C₈ alkenyl, C₃ -C₈ alkynyl, C₁ -C₈alkoxy, C₃ -C₈ alkenyloxy, C₃ -C₈ alkynyloxy, or C₁ -C₈ mono- ordi-alkylamino; C₃ -C₇ cycloalkyl, C₃ -C₈ cycloalkyloxy, C₃ -C₈cycloalkylalkoxy, C₃ -C₇ cycloalkyl C₁ -C₆ alkyl, C₃ -C₇ cycloalkenyl,unsubstituted or substituted by C₁ -C₆ alkyl or C₇ -C₈ phenylalkyl; orc) aryl, aralkyl, aryloxyalkyl, or cycloalkylaryloxy wherein each alkylmoiety contains from 1 to 10 carbon atoms and each aryl moiety isnaphthyl, phenyl or phenyl substituted by one or more halo, C₁ -C₈alkyl, carboxyl, C₁ -C₈ haloalkyl, C₁ -C₈ alkylthio, phenyl, nitro,amino, C₁ -C₈ alkoxycarbonylamino, hydroxyl, acetyl, acetyloxy, phenoxy,C₁ -C₈ alkoxycarbonyl or C₁ -C₈ alkylcarbonyl: (d) R⁷ --W--, wherein Wis O, NH or NR^(f) wherein R^(f) is C₁ -C₄ alkyl; and R⁷ is linear orbranched, unsubstituted or halo-substituted C₁ -C₈ alkyl, C₃ -C₈alkenyl, C₃ -C₈ alknyl, C₃ -C₇ cycloalkyl C₁ -C₆ alkyl, C₃ -C₇cycloalkenyl unsubstituted or substituted by C₁ -C₆ alkyl, unsubstitutedphenyl or phenyl substituted by halo, C₁ -C₆ alkyl, C₁ -C₆ alkoxy,carboxyl, C₁ -C₈ alkythio, phenyl, nitro, amino, hydroxyl, acetyl,acetyloxy, phenoxy, C₁ -C₈ alkoxycarbonyl, or C₁ -C₈ alkylcarbonyl;furanylalkyl, tetrahydrofuranylalkyl, oxetanylalkyl, or oxiranylalkyl;e) R⁸ --W--R^(e), wherein R^(e) is a linear or a branched C₁ -C₆alkylidene; W¹ is O or S; and R⁸ is linear or branched C₁ -C₄ alkyl; f)R⁹ R¹⁰ --N --R , wherein R^(e) is as defined above; and R⁹ and R¹⁰ areindependently linear or branched C₁ -C₄ alkyl; ##STR24## wherein R^(e)is as defined above; W² is O, S, NH, NR¹¹ or CR¹² R¹³ ; wherein R¹¹ islinear or branched C₁ -C₄ alkyl; R¹² and R¹³ are independently hydrogenor linear or branched C₁ -C₄ alkyl; and n' and m are independently 1, 2or 3; h) R¹⁴ --O₂ --C--R^(e), wherein R^(e) is as defined above; and R¹⁴is linear or branched C₁ -C₆ alkyl, C₃ -C₆ alkenyl, or C₃ -C₆ alkynyl;or C₃ -C₇ cycloalkyl, C₃ -C₇ cycloalkyl C₁ -C₆ alkyl, or C₃ -C₇cycloalkenyl, unsubstituted or substituted by C₁ -C₆ alkyl; i) U--R^(e)--, wherein R^(e) is as defined above; U is hydroxyl, acyloxy, aryloxy,arylsulphonyloxy, nitro, cyano or trimethylsilyl; j) 1-adamantyl,2-adamantyl or bornyl; k) Ar¹ --R^(e) --, wherein R^(e) is as definedabove; and Ar¹ is phenyl or phenyl substituted independently with one tothree halogen, mono-, di- or tri- halomethyl, nitro, C₁ -C₄ alkyl, C₃-C₄ alkenyl, C₁ -C₄ alkyloxy, C₃ -C₄ alkenyloxy, or C₃ -C₄ alkynyloxy.2. A compound as recited in claim 1 wherein R⁶ is ##STR25## Z² is O orS; and R^(A) isa) fully unsaturated, partially or fully reduced orsubstituted oxathiinyl, furanyl, dithiinyl, dioxinyl, thienyl, thiazoyl,oxazoyl, isoxazoyl, isothiazoyl, thiadiazolyl, pyrazolyl, pyrrolyl,pyranyl, oxathiazinyl, or oxadiazolyl; b) linear or branched C₁ -C₈alkyl, C₃ -C₈ alkenyl, C₃ -C₈ alkynyl, C₁ -C₈ alkoxy, C₃ -C₈ alkenyloxy,C₃ -C₈ alkynyloxy, or C₁ -C₈ mono- or di- alkylamino; C₃ -C₆ cycloalkylor C₃ -C₆ cycloalkenyl; c) phenyl or phenyl substituted by one or morehalo, C₁ -C₈ alkyl, C₁ -C₈ haloalkyl, C₁ -C₈ alkylthio, phenyl, amino,hydroxyl, carboxyl, acetyl, acetyloxy, C₁ -C₈ alkoxycarbonyl, C₁ -C₈alkylcarbonyl or phenoxy; C₇ -C₈ phenylalkyl or C₇ -C₈ phenoxyalkyl. 3.A compound as recited in claim 2 wherein R^(A) isa)dihydro-3-oxathiinyl, furanyl, dihydrofuranyl, thienyl, pyrrolyl,dihydro-2-dithiinyl, or dihydro-2-dioxinyl, which can be substituted byone to three C₁ -C₄ alkyl or C₁ -C₄ alkoxyalkyl groups; b) linear orbranched C₁ -C₈ alkyl, C₃ -C₈ alkenyl, C₃ -C₈ alkynyl, C₁ -C₈, alkoxy,C₁ -C₈ mono- or di-alkylamino, C₃ -C₆ cycloalkyl or C₃ -C₆ cycloalkenyl;or c) phenyl or phenyl substituted by one or more halo, C₁ -C₈ alkyl, C₁-C₈ haloalkyl, C₁ -C₈ alkylthio, carboxyl, amino, C₁ -C₈ alkoxycarbonyl,hydroxyl, C₁ -C₈ alkylcarbonyl, phenyl or phenoxy.
 4. A compound asrecited in claim 3 wherein R⁶ is ##STR26## Z² is O or S; R¹ is hydrogen;fluoro; or methyl;R² is hydrogen, chloro, fluoro, or methyl; R³ ishydrogen or methyl; R⁵ is hydrogen; and R¹⁵ is methyl, ethyl or propyl.5. A compound as recited in claim 2 wherein R⁶ is: ##STR27## Z² is O orS; X¹ is O or S;R¹⁶ is hydrogen, methyl, ethyl, 1,1-dimethylethyl,fluoro, chloro, carboxyl, acetamido, cyano, C₁ -C₆ alkylthio, C₁ -C₆haloalkoxy, C₁ -C₆ acyloxy, (C₁ -C₆ alkoxy)carbonyl, or (C₁ -C₆alkyl)carbonyl; and R¹⁷ and R¹⁸ are independently hydrogen or methyl. 6.A compound as recited in claim 5 wherein R¹, R³ and R⁵ are hydrogen, R²is halogen, and R¹⁶ is hydrogen, methyl, ethyl or 1,1-dimethylethyl. 7.A compound as recited in claim 2 wherein R⁶ is: ##STR28## Z² is O or S;R⁹, R²⁰, and R²² are independently hydrogen or halogen; andR²³ ishydrogen, halogen, C₁ -C₄ alkyl, C₁ -C₄ alkoxy, mono, di- ortri-haloalkoxy, C₁ -C₄ haloalkyl, C₁ -C₄ alkylthio, amino, C₁ -C₈alkylcarbonylamino, hydroxyl, acetyl, acetyloxy, or acetylamino.
 8. Acompound as recited in claim 2 wherein R^(A) is a linear or branched C₃-C₆ alkyl, C₃ -C₆ alkenyl, C₃ -C₆ alkynyl, C₃ -C₆ alkoxy, or C₁ -C₆mono- or di-alkylamino; phenyl, C₇ -C₈ phenylalkyl, C₇ -C₈ phenoxyalkyl,C₃ -C₇ cycloalkyl, or C₃ -C₇ cycloalkenyl.
 9. A compound as recited inclaim 2 wherein Q is --CR³ ═NOR⁴, R^(A) is C₁ -C₄ alkoxy, phenyl, ordihydro-3-oxathiinyl, furanyl, dihydrofuranyl or thienyl substituted byone to three methyl or ethyl groups, R¹ is H, R² is Cl, R³ is H ormethyl, and R⁵ is H.
 10. A compound as recited in claim 9 wherein R^(A)is C₁ -C₄ alkoxy, Z² is S, and R³ is H.
 11. A compound as recited inclaim 9 wherein R^(A) is 2-methyl-3-furanyl, Z² is S, and R³ is H.
 12. Acompound as recited in claim 2 wherein Q is --XR', R^(A) is furanyl,thienyl or dihydro-3-oxathiinyl substituted by one to three methyl orethyl groups; R² is Cl or methoxy; and R' is C₁ -C₄ di-haloalkyl, C₁ -C₄di-haloalkenyl, C₁ -C₄ mono-haloalkenyl, or C₁ -C₆ alkoxyalkyl.
 13. Acompound as recited in claim 12 wherein R^(A) is 2-methyl-3-thienyl or2-methyl-3-furanyl and Z² is S.
 14. A method for treating HIV infectionin a patient, which comprises administering to the patient an effectiveamount of a compound as recited in claim
 1. 15. A method for treating aHIV infection in a patient, which comprises administering to the patientan effective amount of a compound as recited in claim
 2. 16. A methodfor treating a HIV infection in a patient, which comprises administeringto the patient an effective amount of a compound as recited in claim 12.